Introduction

Cerebral Folate Deficiency (otherwise known as CFD) is a specific neurological condition where the levels of a nutrient called 5-methyltetrahydrofolate (5-MTHF) are low within the cerebrospinal fluid (the fluid that is around the brain and spinal cord), even though there are normal levels of folate within the blood. 5-MTHF is a nutrient which is important for energy levels, heart health, neurological balance and fertility.¹ If this deficiency occurs during the neonate or infant period of a child’s life (which is referred to as early onset of CFD), then serious complications can occur that affect the neurological systems or the development of several aspects of the child. However, if there is early recognition and correct and consistent treatment, then the outcomes for a child with CFD can be significantly improved to ensure a more positive quality of life. 

Understanding Cerebral Folate Deficiency

CFD is a neurological disorder which often has a genetic cause, and one of the genes that is typically has a mutation that then cause CFD is called FOLR1. Other common causes for CFD also include some problems within autoimmune processes or secondary to other metabolic disorders.² These causes either affect how the 5-MTHF is transported throughout the body, or lower the concentration of 5-MTHF; both specifically within the cerebrospinal fluid subsection of 5-MTHF.

As previously mentioned within this article, 5-MTHF is responsible for numerous systems within the body. It is an essential nutrient for brain development and several processes that involve the neurotransmitters within the brain (specifically synthesis and myelination). If the levels of 5-MTHF are too low, this is then called a deficiency and can cause negative neurological symptoms if left untreated, which will progressively get worse as that is the nature of CFD.

Neonatal and Infantile Presentation

If a child has CFD, then symptoms may present themselves very early on in life - even within weeks or months after they are born. Some of these initial symptoms can include, but are not limited to:

• Increased levels of irritability
• Low muscle tone (otherwise known as hypotonia)
• Poor or reduced feeding
• Developmental delay
• Seizures

Over time, more symptoms may even manifest themselves, which are typically more progressive symptoms. These progressive loss of skills usually are the loss of motor skills and sometimes the regression of milestones can even occur which is obviously quite distressing and upsetting for parents and families once they see these manifestations. Some other developments that can occur are impairments in both vision and hearing. In the most severe of manifestations of CFD, movement disorders can occur and microcephaly (otherwise known as a smaller head).³ 

Recognition and Diagnosis

Initial questions regarding whether a child has CFD or not will start to be thought of if an infant presents to healthcare professionals with persistent neurological symptoms that cannot be explained, but their folate levels within the blood return with normal results. If a child is presenting with both of these signs and symptoms, a high suspicion of CFD can be assumed. 

To arrive at a definitive diagnosis of CFD, a lumbar puncture needs to be done on the child with suspected CFD. A lumbar puncture is where a needle is inserted, followed by a hollow plastic tube (a cannula) within the spaces between a particular area of the spine, to obtain some samples of the fluid around the spinal cord. When trying to diagnose CFD, the lumbar puncture will be used to measure the levels of 5-MTHF in the cerebrospinal fluid obtained. 

Alongside a lumbar puncture, genetic testing (usually through blood tests) can confirm or deny whether primary causes of CFD (CFD caused by mutations within the genes that help with the transportation of folate throughout the body) are present in anyone with suspected CFD.

The specific diagnostic tests stated above are methods that are able to definitively diagnose CFD however, complementary additional investigations and testing are also useful to support the diagnosis and to gain a wider picture of the individual in a holistic point of view. Some of these additional investigations and tests could be: metabolic screening (through specific blood tests), immune testing for folate receptor autoantibodies (also through specific blood tests), and an MRI of the brain.

Management Strategies

The primary management method for CFD is folinic acid (which is calcium or sodium leucovorin).⁴ This is a medication that can be given to an individual either orally (by mouth) or intramuscularly (by an injection that goes into the muscle space), and has the aim to improve and restore the levels of folate within the central nervous system rather than the folate levels within generalised blood. The dosing of the folinic acid is adjusted based on the severity of CFD and is monitored through cerebrospinal fluid testing (of which will then impact the dosing and a continuous cycle is formed).

Alongside this primary medication, extra medications and/or therapy methods are recommended to be pursued for symptomatic control, such as anti-epileptic medication for the control of seizures. Other support that may be needed can even include nutritional support due to difficulties and concerns with feeding. 

In order to help with more physical concerns and with helping to achieve developmental milestones and needs, traditional therapies are recommended like regular physiotherapy, occupational therapy and speech therapy.⁵

Prognosis and Long-Term Outcomes

The prognosis of someone with CFD is dependent upon how early treatment is started and optimised - the earlier the management starts, then there is a better change of positive outcomes in terms of developmental progress and achieving milestones. However, sometimes there still may be some neurological deficits even when both treatment and management are started and optimised (particularly if the diagnosis of CFD is delayed, therefore causing treatment and management to be delayed).

In the long-term, the monitoring of both neurological status and folate levels are needed across a person with CFD’s lifetime to ensure they are being managed in the best way possible.

Summary

Cerebral Folate Deficiency (CFD) is a severe neurological condition that can be treated in neonates and infants if correctly identified and treated. It is possible to recognise CFD early through both clinical assessments and specific diagnostic testing, coming together to provide an overall picture of the child with CFD.

Management should be initiated early in order to improve the possibility of positive outcomes in terms of both developmental milestones and quality of life for the child with CFD. The specific management in which this is referring to is the initiation of folinic acid therapy in order to restore the folate levels within the central nervous system rather than just general folate levels within the blood.

However, an absolute essential to the management of CFD is the involvement of numerous healthcare professionals across multiple specialities (for example, neurological, orthopaedic, etc.) and multiple areas (for example, medical, surgical, therapies, etc.). Alongside this multidisciplinary approach to management, the engagement of the parents and support system of whom surround the child with CFD daily are key to enable the success of long-term management, care and treatment.

Frequently Asked Questions (FAQs)

What is cerebral folate deficiency, and how is it different from general folate deficiency?

Cerebral folate deficiency (CFD) is where there is a low level of 5-methyltetrahydrofolate (5-MTHF) within the cerebrospinal fluid. It is different from general folate deficiency as, when the blood is tested in someone who has CFD, their blood folate levels are normal. In someone who has general folate deficiency, their blood folate levels will show low levels of folate.

When do symptoms typically appear in newborns and infants?

Symptoms can be seen in newborns and infants with CFD as early as a few weeks or months after being born. The symptoms seen can develop over time or progressively get worse over a longer period of time - there also may be some symptoms that can only be seen or assessed accurately once the child is a little bit older.

How is CFD diagnosed in very young children?

Initially, a blood test will be done to see the folate levels in the blood and in children with CFD this will show a normal result. To then diagnose CFD, a lumbar puncture will need to be done on the child to test the cerebrospinal fluid of the child. This involves putting a needle in the child’s spinal fluid to get some drops of cerebrospinal fluid for testing.

Is CFD always genetic in origin?

CFD does not always come from a genetic cause (if it does, it is typically due to a mutation within the FOLR1 gene). Other causes of CFD include some issues with autoimmune processes, and sometimes it can occur secondary to a metabolic disorder.